kidney slides- pathogenesis features of rcc kidney slides- pathogenesis features of rcc

1. Pathogenesis and
Histopathological
features of Renal tumors
Moderator Speaker
Dr. Mahendra Singh Rajneesh kr. Srivastava

2. TUMORS OF THE ADULT KIDNEY
INTRODUCTION
Majority of kidney tumors are arises from epithelium of renal tubules, and
almost two-thirds of these epithelial tumors are clear cell renal cell
carcinoma.
EPIDEMIOLOGY
Kidney cancer is only the 14th most common cancer, accounting for
approximately 2% of all cancers
The incidence has increased substantially over the last 2 to 3 decades,
accompanied by an improved 5-year survival.
The better understanding of molecular genetics of renal tumors has
resulted in progress in the management of renal epithelial neoplasms.

3. WHO CLASSIFICATION
2022
• Renal cell tumors
- Clear cell renal tumors
Clear cell renal cell carcinoma
Multilocular cystic renal neoplasm of
low malignant potential
- Papillary renal tumors
•Renal papillary adenoma
•Papillary renal cell carcinoma
-Oncocytic and chromophobe renal
tumors
•Oncocytoma of the kidney
•Chromophobe renal cell carcinoma

4. - Collecting duct
tumors
•Collecting duct
carcinoma
- Other renal tumors
•Clear cell papillary renal
cell tumor
•Mucinous tubular and
spindle cell carcinoma
•Tubulocystic renal cell
carcinoma
•Acquired cystic disease
associated renal cell
carcinoma
•Eosinophilic solid and
cystic renal cell carcinoma
•Renal cell carcinoma
NOS

5. - Molecularly
defined renal
carcinomas
•TFE3 rearranged renal
cell carcinomas
•TFEB altered renal cell
carcinomas
•ELOC (formerly TCEB1)
mutated renal cell
carcinoma
•Fumarate hydratase
deficient renal cell
carcinoma
•Succinate
dehydrogenase deficient
renal cell carcinoma
•ALK rearranged renal
cell carcinomas
•SMARCB1 deficient
renal medullary
carcinoma

6. Metanephric tumors
•Metanephric adenoma
•Metanephric
adenofibroma
•Metanephric stromal
tumor
Mixed epithelial and
stromal renal tumors
•Mixed epithelial and
stromal tumor of the
kidney
•Pediatric cystic
nephroma

7. Renal mesenchymal
tumors
•Adult renal
mesenchymal tumors
•Classic
angiomyolipoma /
PEComa of the kidney
•Epithelioid
angiomyolipoma /
epithelioid PEComa of
the kidney
•Renal
hemangioblastoma
•Juxtaglomerular cell
tumor
•Renomedullary
interstitial cell tumor
•Pediatric
renal
mesenchym
al tumors
•Ossifying
renal tumor
of infancy
•Congenital
mesoblastic
nephroma
•Rhabdoid
tumor of the
kidney
•Clear cell
sarcoma of
the kidney

8. Embryonal neoplasms
of the kidney
•Nephroblastic tumors
•Nephrogenic rests
•Cystic partially
dedifferentiated
nephroblastoma
•Nephroblastoma
Miscellaneous renal
tumors
•Germ cell tumors of
the kidney

9. Classification of Renal Tumors in Adults

10. Common Genetic Abnormalities in Renal Cell Tumors

12. Syndromic Renal Tumors and Their Associations

13. Immunohistochemistry in Renal Neoplasms

14. HEREDITARY RENAL TUMORS
 Five to 8% of all RCCs are hereditary
 Renal tumors with relatively high incidence of hereditary basis
include, among others,
 clear cell RCC (most common association with VHL syndrome),
angiomyolipoma (AML),SDH mutation–associated RCC (SDH
syndromes),
 Fumarate hydratase deficiency-associated RCC (HLRCC syndrome)-
Because of somatic mutations in FH gene in some tumors, FH-
deficient carcinoma is now the preferred term
 A variety of predominantly eosinophilic tumors (BHD syndrome,SDH
syndrome)

15. SUCCINATE DEHYDROGENASE (SDH)–DEFICIENT RCC
 SDH-deficient renal cell carcinoma is one of the manifestations of hereditary
paraganglioma/pheochromocytoma syndrome, which is characterized by
multiple tumor types including pheochromocytomas, extra-adrenal
paragangliomas, gastrointestinal stromal tumors (GIST), renal cell
carcinomas, and rarely testicular seminomas, neuroblastomas, and thyroid
tumors.
 The syndrome is autosomal dominant and shows mutations in Succinate
dehydrogenase (SDHA, SDHB, SDHC, SDHD) genes (located at 5p15, 1p36,
1q21, and 11q23, respectively) or gene assembly factor (SDHAF) (11q12)
 SDH gene complex encodes for SDH enzyme, a mitochondrial complex II
enzyme, required for oxidation of succinate to fumarate in Krebs cycle.
 Pathogenesis - SDH enzyme dysfunction leads to elevated levels of succinate
that moves from mitochondria to cytoplasm and causes competitive inhibition
of HIF (hypoxia-inducible factor)-α prolyl hydroxylase, preventing
hydroxylation of HIF. Accumulation of HIF is known to activate multiple
downstream pathways, many of which are known to be associated with
tumorigenesis. The vast majority of SDH-deficient RCCs show mutations in
SDHB gene, whereas mutations in SDHC, SDHD, and SDHA are much less
common

17.  SDH-deficient RCCs are rare
 Estimated incidence of 0.05% to 0.2% of all resected renal cell tumors.
 In SDH syndrome, approximately 14% of the patients have the risk of
developing RCC by the age of 70 years.
 Mean age at presentation for RCC is approximately 37 years
 RCCs are bilateral in approximately 25% of patients with renal tumors
Gross appearance
 Mean tumor size ranges from 4.3 to 5.1 cm
 Most are well circumscribed, often with pushing border, and sometimes
associated with pseudocapsule,
 Rarely, the tumor may show infiltrative edges, and such tumors often reveal
high-grade features on microscopy

18. Microscopy
 The majority of SDH-deficient RCCs shows a compact nested or sheet-like
architecture, and is composed of medium-sized cells with eosinophilic,
sometimes finely vacuolated cytoplasm.
 Microcysts are fairly common. Nuclei are typically uniform and round, with
smooth nuclear contours, finely clumped chromatin, and small or absent
nucleoli. Cytoplasmic inclusions (mostly single) containing pale eosinophilic or
even pale/clear material are frequent but may be inconspicuous or absent
(Fig. 42.3).
 IHC for SDHB is negative whenever there is inactivation of any of the SDH
genes, which is almost always associated with germline mutation in one allele
with a somatic second hit in the other allele.
 Because SDH is a mitochondrial enzyme, positive (retained) SDH staining is
cytoplasmic and granular

19. Fumarate hydratase–deficient RCC
Showing presence of nuclei with large
nucleolus surrounded by a clear halo.
IHC shows the complete loss of FH
staining in the tumor cells, while
internal control (endothelial and
inflammatory cells in the tumor)
retains the positivity
SDH B–associated RCC composed of
cells with eosinophilic cytoplasm and
showing the characteristic
cytoplasmic inclusions.
SDHB IHC shows complete loss of the
cytoplasmic positivity, with retained
staining in internal controls

20. FUMARATE HYDRATASE–DEFICIENT RENAL CELL CARCINOMA
 The majority of fumarate hydratase (FH)–deficient RCCs are hereditary, and a
part of hereditary leiomyomatosis renal cell carcinoma (HLRCC) syndrome .
 Most cases with renal tumor present young with a mean age between 36 and
46 years,
 HLRCC is an autosomal-dominant syndrome, characterized by Fumarate
hydratase (FH) gene (located at 1q42.3-q43) mutations (281 288).
 Most hereditary cases have germline missense mutations in one allele of the
gene, accompanied by missense mutation or deletion of the other allele .
 Most patients develop leiomyomas of the skin and uterus at young age, and
occasionally leiomyosarcoma of uterus.
 There is lower level of genetic penetrance for RCC with only 20% to 35% of
the patients with the mutation developing RCC.
 Very rare cases of bladder cancer and Leydig cell tumors of the testis
Pathogenesis - FH deficiency leads to fumarate accumulation in the cells,
competitive inhibition of prolyl hydroxylase domain–containing proteins (PHDs),
prevention of hydroxylation of HIF-1, stabilization of the HIF-1alpha complex,
and ultimately carcinogenesis.

21.  The tumors show very aggressive clinical behavior, often with metastases at
presentation (>60%, usually to regional lymph nodes, lungs, bones and liver),
even when small in size
 Most often the tumor is unifocal, unlike that seen in most other syndromes,
although rare multifocality has been observed. Morphologically, the tumors
often show a combination multiple architectural patterns, with variable, but
often prominent, papillary architecture. The papillary cores are often
hyalinized and lack foamy macrophages. Other common architectural
patterns include solid alveolar, tubular/glandular, tubulocystic, sheet-like and
sarcomatoid . Tumor cells are large and often with abundant eosinophilic
cytoplasm; rarely focal clear cell change may be present. Most diagnostic and
consistent feature is the presence of large nuclei with very prominent
orangophilic or eosinophilic nucleoli, surrounded by clear perinucleolar halo
 By immunohistochemistry, fumarate hydratase expression is completely lost in
almost all tumors
 While FH may not be completely absent in rare FH-deficient tumors, diffuse
nuclear and cytoplasmic overexpression of 2SC (S-[2-succino]-cysteine), a
product caused by aberrant succination of proteins due to high level of
accumulated fumarate in the tumor cells is often present in such cases

22. CLEAR CELL RENAL CELL CARCINOMA
 Clear cell carcinomas comprise approximately 60% of renal tumors .
 Although they are still the most common of all renal cancers, over the past few years, clear cell
RCC as a proportion of all renal cell tumors has shown a declining incidence.
 This is mainly the result of identification and separation of multiple subtypes of RCC, which were
previously included within the clear cell RCC category.
Clinical Features
 Males are affected more commonly than women in a ratio of 1.7 to 2.0:1 with a peak incidence
during the seventh decade of life.
 Hereditary clear cell RCCs tend to arise at an earlier age, usually in the fourth or fifth decade of
life, and are more likely to be bilateral and multifocal.
 In sporadic disease, both kidneys are affected equally and most tumors are solitary.

23. Gross Features
 Grossly, the classic case has a golden yellow color due to abundant intracytoplasmic
lipid.
 Higher-grade tumors contain less lipid and glycogen and show a more variegated
appearance including areas of hemorrhage and necrosis
Gross appearance of a clear cell
renal cell carcinoma shows
sarcomatoid features with transition
between the more typical golden
yellow area and that with a tan-
white color,

24. Microscopic Features
 Microscopically, approximately 50% of cases exhibit exclusive acinar
growth pattern.
 They are characterized by solid acinar structures or nests of tumor
cells, separated by delicate, intricately branching fibrovascular septa.
 In few cases these tumors contain a mixture of growth patterns
including solid sheet-like, cystic, papillary/pseudopapillary, tubular, and
sarcomatoid.
 A rich capillary vascular network is prominent in all but the solid sheet-
like and sarcomatoid areas.
 Growth pattern is loosely associated with grade because most- low-
grade lesions have an acinar growth, whereas higher grade areas are
more likely to exhibit solid, pseudopapillary, rhabdoid, or sarcomatoid
features.

25. Clear cell (conventional) carcinoma, nucleolar grade 1. Grade 2 clear cell carcinoma with pseudopapillary
growth.

26. Clear cell carcinoma showing transition from nucleolar
grade 1 to grade 3 areas. The higher-grade component
has abundant eosinophilic cytoplasm, whereas the lower-
grade area contains clear cytoplasm.

27. MULTILOCULAR CYSTIC RENAL NEOPLASM OF LOW
MALIGNANT POTENTIAL
Multilocular cystic renal neoplasm of LMP,
previously designated as “multiloculated cystic
clear cell RCC”, was considered to be a rare variant
of clear cell RCC constituting between 3% and 6% of
clear cell RCC
 The mean age at diagnosis is 51 years
 Although, it has been shown to be associated with
3p deletions and the silencing of the VHL gene
similar to that in conventional clear cell
carcinomas

28.  The gross appearance is that of a well-circumscribed, multicystic
mass, which is separated from the adjacent renal parenchyma by a
fibrous pseudocapsule (Fig. 42.13). Size can be quite variable but may
reach 13 cm in greatest dimension. The cysts are variable in size, may
contain serous or bloody fluid or clot, and are separated by thin
fibrous septa. By definition, no solid or expansile masses of tumor are
present.
Kidney containing two separate tumors, which do not
merge. On the right side is a chromophobe carcinoma
and on left side is a multilocular cystic renal neoplasm of
low malignant potential (LMP).

29.  Microscopically, the thin fibrous septa are lined by one or several layers of
cells, although in many areas, the epithelial lining may be absent. Foamy
macrophages may also line the cyst wall. Occasionally, the tumor cells exhibit
papillary tufting into the cyst lumen. The tumor cells contain clear cytoplasm
and nucleolar grade 1 or 2 nuclei. Small collections of tumor cells are present
within the fibrous septa (Fig. 42.14) or in the adjacent pseudocapsule, but no
expansile or solid masses of tumor are evident.
Multilocular cystic renal neoplasm of LMP. Variably
sized cysts lined by a single layer of cells with clear
cytoplasm and low-grade nuclei. Note the presence of
small clusters of clear cells in the septa without
forming any expansile nodules

30. CLEAR CELL PAPILLARY RENAL NEOPLASM “OF LOW
MALIGNANT POTENTIAL”
 The tumor was initially described in the setting
of end-stage kidneys and named clear cell
papillary RCC.
 Gross Features Grossly, they are well
circumscribed and usually encapsulated, although
the capsule may be of variable thickness. It is
common for the lesion to be cystic or partially
cystic and partially solid. Areas of apparent
hyalinization are common

31.  Microscopic findings shows –
 The tumor cells have uniformly clear cytoplasm and low-grade nuclei. The cells
are cuboidal to low-columnar and arranged in tight tubular/acinar structures,
particularly in the tumor-bearing solid areas. If the tumor cells have minimal
cytoplasm (collapsed acini), these areas can appear to have a solid, sheet-like
appearance.
 Invariably clear cells also line small, tightly packed papillary structures. In other
cases, the tubules show branching and infoldings, imparting an apparent papillary
architecture. Sometimes these papillary structures are tufting into cystic spaces,
which are also lined by clear cells. Characteristically, the tumor nuclei are
arranged in a linear fashion, away from the basal aspect of the cell, either in the
center of the cell or close to the apical aspect
Clear cell papillary neoplasm/renal cell carcinoma.
Because of their indolent clinical behavior, neoplasm of
LMP is now the preferred term, instead of renal cell
carcinoma. Morphologically, the most characteristic
feature of the tumor

32. PAPILLARY RENAL CELL CARCINOMA
 Papillary renal cell carcinoma (PRCC) is the second most
common subtype of RCC after clear cell RCC
 The term chromophil renal carcinoma has been used to
describe these tumors, but WHO (2016) does not
recommend this name any longer, and papillary renal cell
carcinoma is the universally accepted term for the tumor
 CLINICAL FEATURES PRCCs are reported to comprise 11% to
20% of primary epithelial renal neoplasms
 Age at presentation ranges from the third to eighth
decade of life with peak incidence in the sixth and
seventh decades,
 The male-to-female ratio ranges from 2:1 to 4:1

33.  GROSS FEATURES Tumors appear as a discrete mass within the renal
cortex. Greater than a third of tumors are surrounded by a fibrous
pseudocapsule on gross evaluation. Most tumors exhibit a variegated
cut surface .The color of the tumor in great part is related to the
microscopic findings; tumors containing abundant foamy macrophages
are tan to yellow, whereas those with intratumoral hemorrhage are
dark tan to brown. Some lesions may be frankly necrotic.
Papillary renal cell carcinoma
shows the brown-black
appearance of three of the lesions
is due to intratumoral
hemorrhage, whereas the yellow-
tan appearance is due to the
presence of abundant foamy
macrophages within fibrovascular
cores.

34. MICROSCOPIC FEATURES
 Conforming to the gross circumscription, a majority of PRCCs show a well-
defined fibrous pseudocapsule on light microscopic evaluation. Even when the
capsule is incomplete, most tumors tend to be well circumscribed.
 The majority of PRCCs exhibit a broad morphologic spectrum, including
papillary, tubulopapillary, papillary-trabecular, and papillary-solid areas (174-
171,184). The classic papillary pattern is characterized by discrete papillary
fronds lined by neoplastic epithelial cells and containing a central
fibrovascular core, easily recognized on low magnification (Fig. 42.19). The
papillary-trabecular areas exhibit papillations, which are delicate, elongated,
and arranged in a parallel fashion
 In the papillary-solid areas, the papillae are closely packed, masking their
true growth pattern. The fibrovascular cores and consequently the papillary
nature of the lesion are more difficult to discern, requiring examination under
medium-to-high magnification. In cases exhibiting delicate fibrovascular cores
devoid of foamy macrophages, these tumors may be mistaken to have a solid
growth patter

35. Papillary renal cell carcinoma. Fibrovascular cores
contain abundant histiocytes and many tumor cells are
laden with hemosiderin

36. Papillary renal cell carcinoma. Fibrovascular cores do not
contain macrophages and the papillae are compressed,
imparting the tumor a trabecular growth pattern.

37. Papillary renal cell carcinoma showing a combination of
so-called type 1 and type 2 features within the same
field.

38. Distinguishing Features in Common Renal Tumors with Papillary Architecture

39. CHROMOPHOBE RENAL CELL CARCINOMA
 Chromophobe renal cell carcinomas (CRCCs) are arise from intercalated cells
of the renal cortex, similar to oncocytomas.
 CRCCs comprise 6% to 11% of renal epithelial tumors.
GROSS FEATURES
 Characteristically, these tumors are well circumscribed but not
encapsulated
 Classic cases show a homogeneous beige or pale-tan cut surface
 rare tumors are dark brown and mahogany; such tumors often turn out to be
the eosinophilic variants.
 Tumors commonly have a lobulated appearance and roughly one-fifth of cases
exhibit gross necrosis.
 Cystic areas are rare as well as evidence of multifocality is also rare
 Grossly renal vein involvement seen in a small number of cases, whereas in a
very few cases may invade renal sinus or perirenal adipose tissue

40. Chromophobe renal carcinoma. Showing .lobulated mass
with areas of hemorrhage and necrosis. Central scar also
seen here

41. MICROSCOPIC FEATURES
 Mostly the tumors are nonencapsulated
 The pattern of growth is predominantly solid sheet-like, separated by thin,
incomplete fibrovascular septa
 It may be focally admixed with tubular, nested, broad alveolar, trabecular,
solid, cystic, or papillary patterns .A small percentage of cases may exhibit a
sarcomatoid pattern of growth
Immunohistochestry
• Tumor cells show immunoreactivity for EMA as well as pankeratins such as
CAM 5.2 and AE1/AE3.
• Expression of CK7 is usually diffuse and strong. However, CK7 positivity may
be very focal or even absent in the eosinophilic variants.
• Vimentin is positive only in the sarcomatoid areas.
OUTCOME- The prognosis of CCRC is much better than other types of RCC

42. Chromophobe renal cell
carcinoma demonstrating a
solid growth pattern with
incomplete septations and
cells with hyperchromatic,
irregular nuclei and
perinuclear clearing
Chromophobe renal carcinoma
with focal papillary growth.
CRCC with sarcomatoid features.

43. RENAL ONCOCYTOMA
 Oncocytoma is a benign renal epithelial neoplasm first described by
Zippel in 1942
 It is estimated that oncocytomas comprise from 3.2% to 7% of all
primary renal neoplasms
GROSS FEATURES
 Oncocytomas are well-circumscribed, nonencapsulated neoplasms
that are classically mahogany brown and less often tan to pale yellow
 The presence of a central, stellate, radiating scar is seen in roughly
33% of cases and is related to size.
 Gross hemorrhage is present in 20% of cases but necrosis is almost
nonexistent
 Cysts and gross extension into perinephric adipose tissue are rarely
seen.
 Multifocal tumors are seen in up to 17% of cases and bilateral tumors
in 4%

44. Oncocytoma. The tumor is dark tan/brown with a central
area of scarring

45. MICROSCOPIC FEATURES
 The architectural appearance is variable and consists of solid compact
nests, acini, tubules, or microcysts embedded within a hypocellular,
often hyalinized stroma .The predominant cell type is round to
polygonal with granular eosinophilic cytoplasm, round and regular
nuclei with evenly dispersed chromatin, and a centrally placed
nucleolus. A population of smaller cells with scanty granular
cytoplasm, a high nuclear-to-cytoplasmic ratio, and dark
hyperchromatic nuclei (so-called oncoblasts) may also be present
.Such tumors are called as small cell variant of oncocytoma
 If dilated tubules or microcysts are present, they may be filled with
red blood cells .Occasional clusters of cells with pleomorphic and
hyperchromatic nuclei are common ,these most likely represent
degenerative changes

46. High-power magnification of renal
oncocytoma. Notice the densely eosinophilic
cytoplasm and regular round nuclei with
easily identifiable nucleoli
Oncocytoma containing a population of
cells with scanty cytoplasm, a high
nuclear-to-cytoplasmic ratio, and small
hyperchromatic nuclei (so-called
“oncoblasts”)

47.  Mitotic activity is rare
 Necrosis and atypical mitotic figures are not seen.
 Focal clear cell change may be present in areas of stromal
hyalinization and these foci may superficially resemble
clear cell RCC.
 Although small papillae or intratubular epithelial tufts
may be seen focally in up to 27% of cases, pure or
extensive papillary architecture is not a feature of renal
oncocytoma
 Microscopic extension into perinephric adipose tissue is
seen in up to 20% of cases and vascular invasion in as
many as 5%

48.  RENAL TUMORS OF BIRT-HOGG-DUBÉ SYNDROME Renal tumors in the rare,
autosomal-dominant BHD syndrome are usually multifocal and bilateral. Most
tumors have oncocytic features and have been considered to be oncocytoma,
CRCCs, or tumors with hybrid features of renal oncocytoma and CRCC (
Bert-Hogg-Dubé syndrome–associated renal cancer with
clusters of cells with clear cells dispersed in a
background of predominantly oncocytic cells.

49. Distinguishing Features of Renal Oncocytoma and Chromophobe Renal Cell Carcinoma

50. OTHER TUMORS (INCLUDING RECENTLY DESCRIBED) WITH EXCLUSIVE OR
PREDOMINANT EOSINOPHILIC CYTOPLASM
Summary Features of the New, Emerging and Provisional Eosinophilic Renal Entities

51. ESC RCC. Showing compact acinar/nested
growth pattern with dispersed cysts and
cells with eosinophilic cytoplasm with
significant nuclear atypia.Tumor is often
positive for CK20
Eosinophilic vacuolated tumor. The tumor is composed of
solid to nested growth with many cells containing
variable-sized intracytoplasmic vacuoles.

52. Low-grade oncocytic tumor (LOT). Showing tightly packed small nests of cells
with dense, eosinophilic cytoplasm. However, the tumor is consistently
CD117 negative and often shows diffuse CK7 positivity

53. COLLECTING DUCT CARCINOMA
 COLLECTING DUCT CARCINOMA also known as Bellini duct carcinoma, is rare,
comprising less than 1% of renal epithelial tumors
CLINICAL FEATURES
 CDC may occur at any age, the mean age at presentation approximating 50
years
 Hematuria is the most common symptom at presentation, followed by pain,
weight loss, the presence of a palpable mass, and symptoms related to the
site of metastasis. The aggressive nature of most of these tumors is evidenced
by the fact that more than 50% present with metastatic disease.
GROSS FEATURES
 CDCs are centered in the medulla, although large tumors may occupy the
cortex as well (Fig. 42.45). They are unifocal, solid, tan-white, and firm but
may contain cysts as well as gross evidence of hemorrhage and necrosis. The
tumors are poorly circumscribed and often extend into renal sinus and hilar
fat. FIGURE 42.45 Collecting duct carcinoma. The tumor is located in the
medullary portion of the ki

54. Collecting duct carcinoma. The tumor is located in the
medullary portion of the kidney and spares the cortex. A
regional lymph node is enlarged and replaced by tumor.

55. Microscopic findings
 The histologic features of classic tumors, as stated above, are those of a high-
grade adenocarcinoma, often with nodular configuration, tubular and
tubulopapillary architectural patterns, neoplastic ducts, tubules, and papillae
in a fibrotic or desmoplastic stroma (Fig. 42.46) (253-256).
 Focal spindle cell differentiation is not unusual and rare cases may be frankly
sarcomatoid (267-270). The papillae only rarely contain foamy macrophages,
but intratumoral chronic inflammatory cells are usually abundant. Psammoma
bodies are rare. Lymphovascular invasion is present in practically all tumors.
Characteristically, dysplastic or neoplastic cells may be present in adjacent
renal tubules. Cytoplasmic and luminal mucin is characteristic of these
tumors and is a helpful distinguishing feature.
 Immunohistochemical profile that includes immunoreactivity for CEA, peanut
lectin agglutinin (PNA), and Ulex europaeus agglutinin (UEA).
 CK 34BE12 and CK7 may be positive, as well
 OUTCOME Classic CDC cases are characterized by aggressive behavior. Greater
than 90% of cases have pT3 or pT4 disease at presentation (274). More than
50% present with metastatic disease and the median survival after diagnosis is
44 weeks

56. Collecting duct carcinoma. Tubular and solid structures
are lined by tumor cells with high-grade nuclei. The
tumor is frequently associated with marked stromal
desmoplasia.

57. RENAL MEDULLARY CARCINOMA
 first described renal medullary carcinoma in 1995—a unique group of tumors
affecting predominantly young patients of African American, Mediterranean or
other ancestry descent with sickle cell trait.
 Age -Patients range in age from 8 to 58 years with a mean of 22 years
 Males are affected predominantly
 Pathogenesis - The greater length of the right renal artery, resulting in lesser
blood flow and relative hypoxia in the right kidney.
 The hypoxic and hypertonic environment of the renal medulla, combined
with microvascular occlusion by sickled erythrocytes, could promote the DNA
double-strand breaks, which further causes deletions and translocations
inactivating SMARCB1
 Renal medullary carcinomas are centered in the medulla of the kidney, have
distinctive morphologic features, and follow a very aggressive clinical course.
They are believed to arise from the distal portions of the collecting ducts.
 Microscopically these tumors are composed of cells with high-grade nuclei and
prominent nucleoli, often showing cribriforming glands and islands of
anastomosing tubules and cords, frequently forming irregular microcystic
spaces that impart a reticular appearance

58. Tumor cells are arranged in nests and
cribriform sheets and exhibit high grade nuclei
and variable amounts of eosinophilic or
amphophilic cytoplasm. The stroma is
desmoplastic and contains many inflammatory
cells, predominantly neutrophil.
The sickled red blood cells in a vessel next to
the tumor
Medullary carcinoma with an endodermal sinus–like
growth pattern.
IHC reveals complete loss of expression of Baf47 (INI1) in
the tumor cells, whereas the positivity is retained in
inflammatory and endothelial cells

59. MIXED EPITHELIAL AND STROMAL TUMOR (MEST)/ADULT-TYPE
CYSTIC NEPHROMA
 These are multicystic to solid and cystic biphasic tumors
of the adults
 MEST, composed of mesenchymal (stromal) and epithelial
components, shows a combination of solid and cystic areas
in variable proportions. the adults
 Clinical features - Patients have ranged from 19 to 84
years of age, and females have outnumbered males by a
10 or more to 1 margin (326,331). Presenting signs and
symptoms most commonly include a palpable abdominal
or flank mass, flank pain, or hematuria although most
tumors are detected incidentally

60. GROSS FEATURES
 Grossly, MEST are solid or solid and cystic, tan to yellow, well
circumscribed and encapsulated, and range in size from 2 to 24 cm.
 Cystic nephroma grossly is well circumscribed and composed of
multiple, noncommunicating cysts that vary in size and contain clear
fluid.
 Involvement of the renal hilum and compression of the pelvicalyceal
system is common; Rarely, the tumor may protrude into the
pelvicalyceal system
 however, gross infiltration into adjacent renal parenchyma is not
seen.
 Solid expansile mural nodules, hemorrhage, and necrosis are not
found in cystic nephroma

61. Gross appearance of Adult-type cystic nephroma. showing
a well-circumscribed multilocular cystic neoplasm

62. MICROSCOPIC FEATURES
 Microscopically, mixed epithelial and stromal tumor is biphasic, composed of
mesenchymal (stromal) and epithelial components
 . It is characterized by fascicles and sheets of spindle cells showing variable
degrees of smooth muscle, fibroblastic, or myofibroblastic differentiation
with interspersed collagen.
 Mitotic figures, hemorrhage, and necrosis are uncommon.
 The epithelial components vary from round and regular tubules to more
complex structures, which show papillations and cystic dilatation. They are
lined by cuboidal-to-flattened epithelium that may show clear cell change or
have a hobnail appearance
 The epithelial components may be found interspersed throughout the
mesenchymal components and not merely restricted to the periphery of the
tumor nodules.
 In cystic nephroma, the cysts are lined by flattened, cuboidal, or hobnail
cells, and the septa are composed of fibrous tissue of variable cellularity
 The immunohistochemical profile of the mesenchymal components reflects
the degree of smooth muscle differentiation seen on routine hematoxylin-
and-eosin–stained sections.
 The epithelial components are positive for both low- and high-molecular-
weight CKs and U. europaeus, as well as Pax8 .

63. MEST Biphasic appearance with mesenchymal and
epithelial components is evident

64. WILMS TUMOR (NEPHROBLASTOMA)
 WT is the most likely consideration for any pediatric renal neoplasm,
except during the first 3 months of life.
 WT has a peak incidence between the ages of 2 and 5 years, with 90%
being diagnosed by age 6 years
 ported in the literature and delay in diagnosis (12). Several
dysmorphic syndromes are associated with a high risk of developing
this neoplasm
 The WT1 gene, located on chromosome 11p13, is consistently involved
in the pathogenesis of the WAGR syndrome (WT associated with
aniridia and genital anomalies) and the Denys-Drash syndrome
(pseudohermaphroditism, severe glomerulopathy, and WT).
 second WT locus maps to 11p15, where multiple imprinted candidate
genes reside, including IGF-2, p57KIP2, and KV LQT1. This locus is
implicated in the Beckwith Wiedemann syndrome.

65.  somatic genetic alterations have been identified in WT.
Inactivation of a tumor-suppressor gene on the X
chromosome, WT-X (AMER1), has been demonstrated in
one-third of WTs
 WTs demonstrating loss of heterozygosity for chromosomes
1p and 16q have been shown to have a poor prognosis
 TP53 mutations are closely linked with anaplasia and
worse outcome
 The prognosis for WT has dramatically improved from
approximately 8% survival at the beginning of the century
to more than 90% today. The most common sites of
metastasis are regional lymph nodes, lungs, and liver
(“3L’s”). Spread to other organs is rare, even in advanced
cases.

66. Gross Features
 WT typically presents as a unicentric, spherical mass that is sharply
demarcated from renal parenchyma
 Approximately 10% are multicentric.
 Multicentricity is associated with an increased likelihood of tumor
formation in the remaining kidney.
 Bilateral renal tumors are initially present in 5% to 6% of cases.
 The sectioned surface of WT is usually pale gray and uniform, but
focal hemorrhage, necrosis, and cyst formation are commonly
encountered. The texture is usually soft and friable
 Tumors with abundant stroma may have a dense, myomatous
consistency.
 Calcification is relatively uncommon.
 Prominent septa often impart a nodular appearance
 WT can arise anywhere in the cortex or medulla, usually compressing
and distorting renal parenchyma around its margin. Rarely, exophytic
tumors connected to the renal surface by a narrow pedicle may mimic
extrarenal WT

67. Unicentric, spherical mass that is sharply
demarcated from renal parenchyma
The renal vein and its branches are often filled by tumor thrombus that can extend
via the inferior vena cava into the right atrium.
Multicentric Wilms tumor

68. Microscopic Feature
 Most specimens exhibit the triphasic appearance, including cells of
blastemal, stromal, and epithelial lineage (Fig. 43.8). However,
monophasic and biphasic lesions are relatively common, consisting of
any one or two of these cell lineages
 Blastemal Patterns- The blastemal cells of WT are small, closely
packed cells, with a high nuclear-to-cytoplasmic ratio revealing little
or no evidence of differentiation toward epithelial or stromal cell
types. The nuclei are usually round or oval, with moderately coarse
chromatin, Nucleoli are relatively inconspicuous.
 Diffuse Blastemal Pattern- Monomorphous, relatively noncohesive
sheets of blastemal cells with aggressively invasive margins
characterize this pattern. It is the most consistently aggressive
pattern of WT.
 Immunoreactivity for WT1 protein is typically limited to the blastema
and epithelial components of WT, with the stroma being negative.
Hence, the absence of labeling for WT1, particularly in a stroma-rich
tumor, does not exclude the diagnosis of WT.
.

69. Selected Histologic Patterns Versus Stage Distribution in Wilms
Tumora

70. Wilms tumor: diffuse blastemal pattern, showing
aggressive invasiveness
Triphasic Wilms tumor

71.  GRADING AND STAGING OF RENAL TUMORS
- The most widely used grading system for renal tumors was Fuhrman
grading sytem.This system uses nuclear grades based on nuclear size,
irregularity of the nuclear membrane, and nucleolar prominence
- In 2012, the International Society of Urologic Pathologists (ISUP)
proposed a different grading scheme that was claimed to be a better
grading system for renal tumors, particularly clear cell and papillary RCC
This grading scheme is primarily based on the largest nucleolar size in
the tumor cells
- That is why this system is also termed as “nucleolar grading”
-But in grade 4,the nucleolar size is not taken into consideration at all.
-Along with that extreme nuclear pleomorphism, tumor giant cells with
multinucleation, nuclear multilobulation, or the presence of sarcomatoid
or rhabdoid features in the tumor are considered .

72. TNM staging (8th edition)
 Primary Tumor (pT)
• pTX: primary tumor cannot be assessed
• pT0: no evidence of primary tumor
• pT1-
- pT1a: ≤ 4 cm, confined to the kidney
- pT1b: > 4 cm and ≤ 7 cm, confined to the kidney
• pT2a: > 7 cm and ≤ 10 cm, confined to the kidney
• pT2b: > 10 cm, confined to the kidney
pT3: Tumour extension into major veins or perinephric tissues,
but not into ipsilateral adrenal gland or beyond Gerota's fascia
- pT3a: invades renal vein / branches, perirenal fat, renal sinus fat or
pelvicalyceal system
- pT3b: extends into vena cava below the diaphragm
- pT3c: extends into vena cava above the diaphragm or invades
vena cava wall
- pT4: invades beyond Gerota fascia, including direct extension to
ipsilateral adrenal gland

73.  Regional lymph nodes (pN)
• pNX: cannot be assessed
• pN0: no regional lymph node metastasis
• pN1: regional lymph node metastasis
• Notes:Regional lymph nodes=hilar, caval, aortic
 Distant metastasis (pM)
 pM0- No metastasis
• pM1: distant metastasis, including noncontiguous adrenal
involvement
 AJCC prognostic stage groups
• Stage group I: T1a-1b N0 M0
• Stage group II: T2a-2b N0 M0
• Stage group III: T1a-3c N1 M0, T3a-3c NX-0 M0
• Stage group IV: T4 any N M0, any T any N M1

74.  Histologic grade (G)
• GX: cannot be assessed
• G1: nucleoli inconspicuous or absent and
basophilic at 40x objective
• G2: nucleoli conspicuous and eosinophilic at 40x
but not prominent at 10x objective
• G3: nucleoli conspicuous and eosinophilic at 10x
objective
• G4: marked nuclear pleomorphism, multinucleated
tumor giant cells, rhabdoid differentiation or
sarcomatoid differentiation

75. THANK YOU